A major question posed in the decade of the eighties was related to the observation that while the SC erythrocyte contained a 50:50 proportion of HbS to HbC, with no significant difference in the tendency of HbC versus HbA to polymerize with HbS, the SC erythrocyte sickled. This led to a series of crucial studies, which demonstrated that the pathognomonic feature of HbSC is the presence of unusually high-density reticulocytes. However, these elegant laboratory studies have not yet been translated into clinical interventions and therapy that has ameliorated disease severity in patients with the HbSS genotype does not mean that the same therapy will necessarily prove efficacious for HbSC disease. Based on innovative studies at our Center related to both adhesion marker analyses, relationships between hematocrit/adhesion/vaso-occlusion, and novel statistical methods of evaluating home pain diary data, we have identified two interventions, which may be helpful for this disorder. We are therefore proposing an approach to therapy with the pleotropic drug hydroxyurea and periodic phlebotomy (HUP Trial). The goal of this clinical trial is to determine whether oral hydroxyurea (HU) therapy and periodic phlebotomy, compared to HU alone over an 28 month period will decrease self-reported pain rates in symptomatic patients > 15 years of age with HbSC disease, as measured by an increase in the median duration between painful episodes. A secondary aim is to determine whether there will be signs of amelioration of organ damage as a result of these therapies; such as a potential partial return of splenic function, or nonprogression of proliferative retinopathy and/or avascular osteonecrosis in previously affected patients. As a third aim, we hope to determine whether "responders" will be able to be differentiated from "non-responders" by specific biologic parameters. Such markers will include red cell indices, dense cell formation, assays and markers for red cell-endothelial adhesion, white cell, endothelial and hemostatic activation, and nitric oxide metabolites. These studies should provide insights into the modes of action of the pleotropic drug hydroxyurea, as well as preliminary data related to the benefits of phlebotomy. The study can be completed within a 21-month period, and will involve a sample size that can be realistically accomplished within the framework of the 10 Comprehensive Sickle Cell Centers.